Effects of Combined Interventions of Exercise and Diet or Exercise and Supplementation on Breast Cancer Patients: A Systematic Review

This systematic review investigated the effects of exercise interventions combined with diet and/or dietary supplement interventions on anthropometry, body composition, metabolic biomarkers, physical function, healthy lifestyles, quality of life, psychosocial variables and fatigue for women with breast cancer. A systematic search was performed in the PubMed and Web of Science databases (from inception to 1 March 2022). A review was carried out following the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) guidelines. The methodological quality and the risk of bias of the included studies was assessed with the Physiotherapy Evidence Database (PEDro) scale. A total of 13 randomised controlled trial studies were included, comprising 1569 breast cancer patients. The main finding of this systematic review is that groups performing interventions combining exercise plus diet show significant improvements in cardiorespiratory fitness, muscular strength, body composition, quality of life, fatigue, anxiety, depression and sleep compared to control groups. On the other hand, the use of interventions combining exercise plus supplementation does not result in an improvement compared to groups using exercise alone or supplementation alone.


Introduction
Breast cancer (BC) was the most diagnosed cancer in 2020, with an estimated 2.26 million new cases, representing 12.5% of all cancer cases in the world [1]. It had been estimated that in 2022 the number of women diagnosed with BC in Spain would be 34.750 [1]. However, the 2022 reality may be slightly different, as this estimate does not include the possible effect of the COVID-19 pandemic [1].
Physical activity (PA), diet and weight management play a major role among BC patients. The numerous benefits of PA in prevention during treatment and survival have been well documented. In 2018 the Physical Activity Guidelines Advisory Committee review concluded that there is strong evidence for the influence of PA on decreasing risk in seven types of cancer including BC [2]. Moreover, exercise, and specifically aerobic and resistance exercise, is shown to have positive influence on cardiopulmonary function and several biomarkers (i.e., insulin, leptin, Tumour Necrosis Factor alpha (TNF-α) or sex hormone binding globulin), bone loss, body composition, depression and anxiety, and quality of life (QoL), among other factors, during BC treatment [3][4][5]. Although the real impact of PA on the risk of relapse and cancer mortality is not well defined, the evidence

Study Selection and Data Extraction
In a first step, any duplicates were manually removed. Then, the titles and abstracts of articles were checked for relevance by two researchers (T.P.B. and M.A.). They subsequently, independently from each other, reviewed the full texts of potentially eligible articles. Any disagreements were discussed with a third researcher (A.F.S.J.) until consensus was reached.
The authors, publication date, number of patients, age of patients, cancer stage, cancer treatment, dietary supplement(s) and dosing regime, details of dietary intervention, information on the exercise intervention (training type, training frequency, training intensity, supervision, setting), duration of the program, list of outcome variables and main statistical results (changes from baseline within and/or between groups) were extracted from the studies by two authors (T.P.B. and M.A.) independently. If there were disagreements in data extraction, authors discussed until a consensus was reached.

Quality Assessment and Risk of Bias
The Physiotherapy Evidence Database (PEDro) scale was used for the assessment of the risk of bias among the included studies. The PEDro scale is a valid measure of the methodological quality of the clinical trial [23]. Two authors (T.P.B. and M.A.) independently scored the studies and a third author (A.F.S.J.) was recruited in cases of any argument. The PEDro scale consists of 11 items including external validity (item 1), internal validity (items 2-9) and statistical reporting (items 10 and 11) and each one of them contributes 1 point to a total score of 10, excluding item 1. The following cut-points were used to categorise studies by quality: excellent (9-10); good (6)(7)(8); fair (4)(5); poor (<4) [24].

Study Selection
Overall, 1090 records were identified through all database searches. After 171 duplicates had been removed, titles and abstracts from the remaining 919 records were screened and the full text of 568 was assessed for eligibility. Finally, 13 studies were included in this systematic review describing 12 interventions [25][26][27][28][29][30][31][32][33][34][35][36][37] (i.e., one intervention published 2 studies showing its results). We were forced to discard one study conducted by Arikawa et al. [38] because the p-values were not reported, even though some variable changes, body mass and fitness level, were listed as significant in the body of the article. After writing to the authors for p-values and receiving no response, we did not include the results of this study in this systematic review, but they will be mentioned in the corresponding sections of the discussion.
A comprehensive flow diagram of the study selection process is presented in Figure 1.

Study Characteristics
Characteristics of the included studies are presented in Tables 1 and 2.

Study Characteristics
Characteristics of the included studies are presented in Tables 1 and 2.

Diet Interventions
Of the 12 interventions included, 8 used a combined diet and exercise intervention (66.6%).

Supplement Interventions
Of the 12 interventions included, 4 used a combined supplement and exercise intervention (33.3%).

Outcome Measures and Results of Included Studies
The results of the studies receiving exercise plus diet interventions and exercise plus supplementation interventions are presented in Tables 4 and 5, respectively. In addition, a summary table has been added to facilitate the understanding of the results (Table 6).
Isometric muscular strength was measured using handgrip test [29,32] and wall-squat test [32], isokinetic muscular strength was measured using velocity spectrum evaluation [37] and dynamic muscular strength was measured using Chair-Stand test [32] and 10 vertical jumps test [27]. One intervention also measured dynamic muscular strength using chest press and leg extensions exercises; however, the type of protocol used was not specified [29]. Muscular power was determined using the 10 vertical jumps test [27], and muscular endurance was measured using Sit-to-Stand test at 15 and 30 s [26,27]. CRF was analysed using the following tests: 12-min Walking Test (12MWT) [28], 8-min Walking Test (8MWT) [36] and 6-min Walking Test (6MWT) [32]. The following lung function variables were measured directly with a gas analyser: Peak Oxygen Uptake (VO 2peak ) [33] and Maximal Oxygen Uptake (VO 2max ) [35]. One intervention also reported VO 2max but did not specify how it was determined [29].

Healthy Lifestyles
Healthy lifestyles were analysed in 8 of the 12 interventions (66.7%). The variables studied were amount of physical activity [26][27][28]32,33,35], dietary intake [26,27,35,36] and sleep quality [31]. In 8 of the 8 interventions (100%) significant improvements were observed in amount of physical activity [26][27][28]32,33,35], dietary intake [26][27][28]35,36] and sleep quality [31]. In one intervention, both the EG and the CG improved in the total amount of physical activity, but no significant differences were found between the two groups [32]. More specifically, with respect to the amount of physical activity, the results were as follows: an increase in moderate recreational activity or leisure time [26,27]; a decrease in inactive time and an increase in active time [33]; and an increase in the sport/exercise index [35]. Regarding dietary intake, in the different interventions, an increase in the consumption of fibre [26,35] and fruit/vegetables [35], and a decrease in the consumption of alcohol [26], animal protein [26], total fat [28,36], saturated fat [28,36] and energy intake [28,35] were found.
Dietary intake was evaluated using food records, the amount of physical activity was measured using a Global Physical Activity Questionnaire [26,27], the Godin Leisure-Time Exercise Questionnaire [32], the Habitual Activity Estimation Scale [33], the Kaiser Physical Activity Survey [35] and a pedometer [28]. On the other hand, sleep quality was measured using the Pittsburgh Sleep Quality Index [31].
Depression was measured using Hospital Anxiety Depression Scale [26,27] and the Beck Depression Inventory-II [34], Anxiety was measured using Hospital Anxiety Depression Scale [26,27] and Stress was measured using the Perceived Stress Scale [34]. Regarding the Economic Evaluation, both the home group (£7737) and the community group (£7914) had reduced patient costs with respect to the control group (£8547). This is largely due to the reduction in medication to treat toxicity, fewer physiotherapy visits and fewer accidents and emergency visits [28].

Fatigue
Fatigue was analysed in 4 of the 12 interventions (25%). In 2 of 4 interventions (50%) a significant improvement in Fatigue was observed [27,31]. The interventions that measured fatigue using the MFI showed improvements in the following items: General Fatigue [27], Physical Fatigue [27], Mental Fatigue [27], Reduced Activities [27] and Reduced Motivation [27]. On the other hand, the intervention that measured Fatigue using CFS showed a significant improvement in the Fatigue overall score [31].

Discussion
This systematic review investigates the effects of exercise interventions combined with diet and/or dietary supplement interventions on Anthropometry, Body Composition and Metabolic Biomarkers, Physical Function, Healthy Lifestyles, QoL, Psychosocial Variables and Fatigue on women with breast cancer. The main finding of this systematic review is that groups performing interventions combining exercise plus diet show significant improvements in CRF, muscular strength, body composition, QoL, fatigue, anxiety, depression and sleep compared to control groups. On the other hand, the use of interventions combining exercise plus supplementation does not result in an improvement compared to groups using exercise alone or supplementation alone.
We have not found any systematic review that has analysed the effects of a combined intervention of exercise and/or dietary supplementation in breast cancer patients. To the best of our knowledge, there are two systematic reviews with meta-analysis [39,40] and one systematic review [41] that studied the effects of exercise in combination with a nutritional intervention in breast cancer patients on weight loss and biomarkers of inflammation. Our systematic review presents similarities with these three papers: (1) exercise interventions varied greatly, (2) combined diet plus exercise interventions showed improvements in the variables studied. However, our systematic review also presents some differences: (1) we include exercise interventions plus supplementation (4 RCTs), (2) we only included RCTs with a detailed description of exercise, diet and supplementation interventions, (3) we included a larger number of variables (our review includes 51 variables, while the other reviews mentioned above include 8 variables [39], 20 variables [40] and 24 variables [41]).
We would like to clarify that there are 2 interventions [27,37] in which the raw data were not included. Two authors, T.P.B and A.F.S.J. made two attempts to contact the corresponding authors using the available e-mail addresses without response. Because of this, when discussing the results of the interventions and calculating the percentages of change these two interventions were not considered.

Anthropometry, Body Composition and Metabolic Biomarkers
Of the 12 interventions, improvements in anthropometry and body composition were found in 6 of 7 (85.7%) [27,28,31,33,35,36]. Our findings show that the combined interventions of diet plus exercise produced an average improvement of 9.9% (5.2-14.5%) in BMI, 1.7% (1.5-3.7%) in BM, 2.6% (1.6-3.6%) in waist circumference, 1.3% (1.1-1.5%) in hip circumference and 5.2% (3.2-7.1%) in FM. Increased BM and FM as well as decreased muscle mass in breast cancer patients has been associated with increased mortality, increased recurrence, decreased QoL and increased tumour-promoting sex hormones [42][43][44][45]. Maintenance of muscle mass is associated with decreased toxicity from chemotherapy and/or radiotherapy and increased anti-inflammatory myokines (e.g., IL-6), and suppresses tumour growth [46]. Several studies with combined diet plus exercise interventions in healthy [47] and breast cancer patients [48][49][50] have shown improvements in BM and FFM. Therefore, in line with the results of the present systematic review, a combined diet plus exercise intervention seems to be a good option to achieve anthropometric and body composition improvements.
The studies that had follow-up after the end of the intervention showed that the gains achieved are not maintained in some cases. In one intervention, after the end of the intervention and after follow-up, 38.7% of the gains in BM, 13.6% in waist circumference and 29.5% in hip circumference were lost [35]. However, in another intervention, the results were the opposite [28]. The results remained without significant change in the following variables, BM improved by 0.1% in the home group and by 0.7% in the community group, hip circumference worsened in the home group by 0.1% and by 0.2% in the community group, waist circumference worsened by 0.2% in the home group and improved by 0.5% in the community group and FM remained at identical values in the home and community groups [28].
One study found no improvement in any variable related to anthropometry and body composition [26]. A possible explanation for not finding any improvement could be that the EG experienced a reduction in total physical activity time (372.29 MET.min/wk) at the end of the intervention but hardly any change in energy intake (−11.73 Kcal). Finally, another intervention reported that FFM worsened at the end of the intervention, although the decline was not significant and worsened significantly after follow-up [28]. A possible explanation could be the fact that this intervention did not include strength work, which has shown improvements in FFM in cancer patients [51].
In the intervention that had to be withdrawn because it did not include the p-values, the EG decreased body mass by 9.4% during the intervention [38].
Of the 12 interventions, 4 of the 8 interventions (50.0%) showed improvement in metabolic biomarkers [28,29,34,36]. The combined interventions of diet plus exercise showed at the end of the interventions an average improvement in TC of 3.3% (3.1-3.5%) in the community group [28] and leptin improved by 7.5% [36]. In an intervention involving 4 groups (control, calcitriol, exercise and a combination of exercise plus calcitriol), a significant improvement in bone formation measured by Bone-specific Alkaline Phosphatase of 34.7% was observed in the group of participants taking calcitriol [29]. It is worth mentioning that this study analysed the data grouping all participants who exercised and those who did not and they also analysed the results grouping all participants who consumed calcitriol with those who did not. It did not analyse the results of the 4 groups with each other [29]. In another intervention, it was found that morning cortisol levels increased significantly (raw data not available) [34].
Regarding metabolic biomarkers, hyperinsulinemia and insulin resistance, as well as increased markers of low-grade inflammation such as IL-6, TNF-α and CRP, together with decreased anti-inflammatory factors such as adiponectin, elevated levels of oestrogens and androgens (i.e., estrone, oestradiol and testosterone) and low levels of sex hormone-binding globulin have been associated with breast cancer risk [52]. High levels of leptin have been associated with an increased risk of breast cancer as well as with a worse prognosis [53]; however, low levels of ghrelin are associated with increased expression of aromatase in adipose tissue and thus with an increased risk of breast cancer [54]. Increased lipids and lipoproteins contribute to the development of cardiovascular disease (CVD) [55,56]. Elevated cortisol levels in the morning and a decrease throughout the day represent the normal response [57], whereas elevated levels in the evening are associated with risk of depression [58]. Higher leukocyte levels appear to be associated with an increased risk of recurrence [59]. BMD decreases in BC patients treated with TC and/or HT, aromatase inhibitors for postmenopausal women and Tamoxifen in premenopausal women. These treatments cause a decrease in oestrogen production, resulting in bone loss [60]. Calcium and vitamin D are important nutrients for bone health [61]. Numerous studies have shown the benefits of combined interventions of exercise plus diet on lipid profile, insulin, adiponectin, leptin and ghrelin [50,54,[62][63][64] in breast cancer patients. Combined interventions of exercise plus diet have also found benefits in markers of inflammation, oestrogens, androgens and SHBP in other patient populations [65]. Exercise program alone in breast cancer patients also found improvements in IGF-1, IGFBP-1 and IGFBP-3 [66] in maintenance of BMD [67].
In one study that had follow-up after the end of the intervention, the results remained unchanged. TC, LDL-C, TG, HOMA-IR improved by 0.2%, 2.6%, 0.6% and 2.3%, respectively, in the community group and systolic blood pressure and insulin worsened by 0.2% and 0.04%, respectively, in community group [28].
In the 4 interventions that did not find significant improvements, the reasons could be the low sample size [33,35], low adherence to exercise and/or diet/supplementation interventions [33,35,37], dietary intervention not tightly controlled [33], food questionnaires that did not adequately capture caloric intake [35] and exercise intensity was low enough to improve BMD [32], which would limit the ability to detect changes. In one intervention, although no significant improvements were detected, the EG lost less BMD than the CG [37].

Physical Function
Of the 12 interventions, physical function was analysed in 9 of them [26][27][28][29]32,33,[35][36][37] and improvements were found in 5 interventions (55.6%) [26][27][28]36,37]. Our findings show that the combined interventions of exercise plus diet produce improvements of 4.4% in muscular endurance [26,27], 8.2% in the community group in 12MWT [28], 3.2% and 1.8% in systolic blood pressure in the community and home groups, respectively [28], 6.7% in diastolic blood pressure [36] and 32.2% in VO 2max [36]. Strength levels improved by an average of 22.9% in hip, knee and wrist flexion and extension [37]. In the study conducted by Arikawa et al. [38], EG improved cardiorespiratory fitness, as measured via a submaximal treadmill test, by 29.4%. The 12MWT improved by a further 2.2% during the 6-month follow-up period [28]. Elevated muscular strength and CRF levels represent a strong predictor of decreased mortality in breast cancer patients [68,69] and, in addition, high blood pressure contributes to the development of CVD [70]. Studies in breast cancer patients using combined interventions of exercise plus diet, exercise plus supplementation or exercise alone produced improvements in blood pressure [71], cardiorespiratory markers [72][73][74] and muscular strength [73][74][75]. Consequently, programs that combine exercise plus diet/supplementation seem to be a good option to improve physical function.
In 4 interventions [29,32,33,35], no significant improvements in physical function were observed, which may be due to displeasure with the measuring device (face masks) that could have caused them to terminate cardiorespiratory tests prematurely [33], less inclination to tolerate maximum discomfort in cardiorespiratory tests [33], low adherence to the exercise program [29,32,35] or low exercise intensity [32,33].
In relation to physical activity levels, in the only intervention that combined exercise plus supplementation, both groups improved activity levels and, although no significant differences were found between the two groups after the end of the intervention, physical activity levels increased by 11.3% and 8.3% in EG and CG, respectively [32]. Two interventions found an increase in time spent in moderate recreational activity or leisure time [26,27].
Another intervention found a 13.4% decrease in "somewhat" inactive time and a 49.5% increase in "somewhat" active time [33]. On the other hand, another intervention found a 133.3% improvement in the sport/exercise index [35]. Two interventions had follow-up periods [28,35]. In one of the interventions, at 12 months, the community group obtained significantly greater increases (43.0%) than the control and home groups and, in addition, was the only group that continued to improve its physical activity levels compared to baseline values [28]. The remaining intervention had a follow-up period of 6 months, resulting in a 48.6% loss of the gains obtained at the end of the intervention; however, levels were still significantly better than at baseline [35].
In the case of dietary intake, one intervention found an increase in fibre intake and a decrease in alcohol and animal protein intake [26]. Regarding total fat intake, two interventions found that a combined exercise and diet program produced a mean decrease of 14.0% (10.4-16.8%) [28,36] and regarding saturated fat intake, a mean reduction of 16.9% (14.2-20.0%) was found [28,35]. Total intake showed a significant mean reduction of 16.2% (11.1-21.3%). Two interventions were followed up on and resulted in a 15.0% increase in fibre intake and a 32.0% increase in fruit/vegetable intake 6 months after completion of the intervention [35]. The other intervention found that 12 months after starting the intervention, total fat intake and saturated fat intake remained unchanged from the end of the intervention in the home group, with decreases of 0.4% and 0.5%, respectively. However, the community group showed additional decreases of 3.8% in total fat intake and 2.5% in saturated fat intake [28].
Finally, only one intervention [31] analysed sleep quality and improved significantly in the EG (−75.6%). It is worth noting that the tool used to analyse sleep quality was the Pittsburgh Sleep Quality Index, where lower scores denote a healthier sleep quality.
These results are important because breast cancer patients are more likely to gain weight during chemotherapy [76] and obesity negatively affects the survival and prognosis of these patients [77]. In this sense, the case-control EpiGEICAM study showed that the adherence to the Western dietary pattern is related to a higher risk of BC (odds ratio (OR) for the top versus (vs.) the bottom quartile 1.46 (95% CI 1.06-2.01)), mainly in premenopausal women, whereas the Mediterranean dietary pattern was related to a lower risk (OR for the top quartile vs. the bottom quartile 0.56 (95% CI 0.40-0.79)), particularly of triple negative tumors and with no differences between pre-and postmenopausal women [78]. Further, one year after surgery, pre-operative physical activity levels were not recovered [79][80][81]. However, this systematic review and the literature has shown how physical activity and dietary interventions might facilitate weight loss [49,82].

Quality of Life
Of the 12 interventions, QoL was analysed in 6 interventions [26][27][28]30,31,33,36] and improvements were found in 5 of them (83.3%) [27,28,30,31,33,36]. At the end of the intervention period, improvements in different dimensions of the EORTC QLQ-C30 Questionnaire such as Global QoL, Physical Function, Role Function, Emotional Function and Cognitive Function were found [27]. In this same EORTC QLQ-C30 Questionnaire, improvements were found in Global QoL, Physical Function, Role Function, Emotional Function, Cognitive Function and Social Function which on average were 42.7% (29.4-58.7%) and an average reduction of 90.3% in breast cancer-related symptoms such as fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea and financial difficulties [30]. Three interventions used the FACT-B Questionnaire and found improvements that on average were 15.1% (9.5-22.6%) [28,33,36]. Finally, an intervention using the EORTC QLQ-BR23 Questionnaire found improvements in the Body Image and Future Outlook subscales improved by 38.2% and 158.3%, respectively [31]. The side effects resulting from breast cancer treatment that patients may suffer could decrease their QoL levels [83]. Exercise ameliorates the side effects of cancer treatment such as sarcopenia, bone loss and cardiovascular disease [84]. Moreover, patients who were able to complete the exercise interventions experienced a sense of achievement and increased self-esteem [85]. All these reported results would positively influence the improvement of QoL. Furthermore, higher quality diets, such as the Mediterranean diet, have a positive impact on the QoL of breast cancer patients, specifically on physical functioning, sleep, pain and general well-being [86]. Weight gain and obesity negatively affect QoL [87], interventions with diet and/or exercise could reverse these negative outcomes [88].
In two interventions where follow-ups were conducted, 2.9% increases in FACT-B were found over the end of the intervention [28] and improvements were found in Global QoL at 6-month follow-up [27] and in Global QoL, Physical Function, Role Function and Social Function at 12 months [27].
In one intervention, no significant differences in QoL were found between the two groups studied [26]. A possible explanation could be that the patients started from similar or even higher baseline values than the general population and therefore finding improvements in QoL would be difficult. For the Global QoL domain, healthy women from the general population obtained a score of 66, as shown by normative data for the EORTC QLQ-C30 health-related quality of life questionnaire based on more than 15,000 participants from 13 European countries, Canada and the United States [89], while the patients' initial score was 68.45 and 69.94 for the EG and CG, respectively [26].
The Sexual Function and Sexual Enjoyment subscales decreased in one of the interventions [31]. Sexual problems are highly prevalent in patients with breast cancer [90]. These sexual problems have been associated with the use of aromatase inhibitors [91] and tamoxifen [92]. Moreover, the surgical treatment, chemotherapy and hormone therapy appear to accelerate the onset of menopause and negatively influence sexual function [93].

Psychosocial Variables
Of the 12 interventions, psychosocial variables were analysed in 4 interventions and improvements were found in all (100%) [26][27][28]34]. The depression and anxiety values improved in all the interventions where they were analysed [26,27,34]. In the only intervention that presented raw data, the improvement in depression was 54.9% while the improvement in anxiety was 25.8% [34]. The other interventions [26,27] showed improvements in depression and anxiety but did not present the raw data. However, a noteworthy aspect was that at 6-month follow-up, the number of patients with a depression score >10 was lower in the EG (54.0%) than in the CG (69.9%) [26]. Regarding economic cost, the home and community groups showed lower costs than the control group, 9.5% and 7.4%, respectively [28].
Breast cancer patients are at increased risk for depression and anxiety [94] and stress [95]. Cancer is a major economic burden on society. Breast cancer alone accounts for 12% of the total expenditure on cancer treatment in the European Union (€126 billion in 2009) [96]. The results observed are in line with exercise interventions which have been shown to improve depression and anxiety in breast cancer patients [97,98]. On the other hand, a correlation has been found between elevated levels of depression and unhealthy diets [99] as well as an increased incidence of depression in overweight or obese breast cancer survivors with low levels of physical activity [100]. Then, the combined interventions of exercise plus diet could have positive effects on psychosocial variables in breast cancer patients.

Fatigue
Of the 12 interventions, fatigue was studied in 4 of them [25][26][27]31] and improvements were found in 2 (50%) [27,31]. At the end of the interventions, the combined exercise plus diet programs produced improvements in different dimensions of fatigue such as physical fatigue, mental fatigue, reduced activities and reduced motivation [27]. Another intervention produced a 64.5% improvement in CFS [31]. In this sense, it is important to highlight that fatigue is a side effect with a high prevalence (27%) in breast cancer patients [101]. Improvements in strength and cardiorespiratory fitness increase functional capacity and muscle mass and decrease fatigue levels [102]. In the same vein, some supplements such as CoQ10 are related to the generation of energy needed to preserve physical function and overall health, improving fatigue in cancer patients [103]. Dietary interventions may help to decrease chronic inflammation by decreasing inflammatory biomarkers such as CRP, IL6 [104] that are associated with fatigue in cancer patients [105].
In one study, no improvement was found after the end of the intervention or in the follow-up period [26]. However, in the follow-up period the EG experienced a smaller increase in fatigue (15%) compared to the CG (20%) [26]. In the other study, both groups experienced a substantial reduction in perceived fatigue; however, no significant differences were found between the two groups. The EG reduced general fatigue and physical fatigue by 28.4% and 32.2%, respectively, while the CG reduced general fatigue and physical fatigue by 20.1% and 32.1%, respectively [25]. In this case, antioxidant supplementation does not add benefit to strength training [25]. Possible causes could be that in both studies, the initial fatigue levels were already low, which could explain the results.

Limitations
The limitations of this systematic review are as follows: (1) the small sample size of the groups (8 of 12 interventions including <100 participants); (2) the heterogeneity of the exercise interventions (e.g., different types, frequency, intensity, type of session, volume of session, type of supervision); (3) the lack or short duration of follow-ups in most interventions; (4) the adherence to exercise in most of the interventions (6 of 12 interventions) was low (<80%); (5) some studies do not present raw data, making it difficult to interpret and present the data [27,37].

Conclusions
The results of this systematic review suggest that interventions combining exercise plus diet show significant improvements in CRF, muscular strength, body composition, QoL, fatigue, anxiety, depression and sleep. According to our analysis, combined exercise plus supplementation programs do not provide greater improvements than programs that employ only exercise or supplementation. Most of the exercise interventions analysed were semisupervised or supervised, multicomponent (mainly strength and cardiorespiratory exercise), 3 to five days a week, with a duration of 24 weeks, with a session duration of 30 min, and developed at patients' homes and exercise or heath care settings. The most used diet was a hypocaloric diet with a macronutrient composition of 30-35% lipids, 50-55% carbohydrates and 10-15% proteins. The supplementation employed was mainly vitamins.
Future lines of research should focus on RCTs with larger sample size, greater homogeneity of exercise interventions, interventions with improved strategies to increase exercise adherence (≥80%) and long-term follow-up periods.